1. Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect
- Author
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Shi Young Park, Hui-Young Lee, Do Sik Min, Gilbert Di Paolo, Cheol Soo Choi, Mee-Sup Yoon, Jang Ho Hur, Claudia Dall'Armi, and Jae Sung Lee
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Genetic Vectors ,Phosphatidic Acids ,Diet, High-Fat ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Oxygen Consumption ,Piperidines ,Non-alcoholic Fatty Liver Disease ,Tandem Mass Spectrometry ,Lipid droplet ,Internal medicine ,Nonalcoholic fatty liver disease ,medicine ,Autophagy ,Phospholipase D ,Animals ,Cells, Cultured ,Chromatography, High Pressure Liquid ,Triglycerides ,Mice, Knockout ,Multidisciplinary ,Microscopy, Confocal ,Chemistry ,Lipid metabolism ,Phosphatidic acid ,medicine.disease ,Lipid Metabolism ,3. Good health ,Mitochondria ,030104 developmental biology ,Endocrinology ,Biochemistry ,Liver ,Hepatocytes ,Benzimidazoles ,Lipid Peroxidation ,Steatosis ,Lysosomes ,Microtubule-Associated Proteins ,Phospholipase D1 - Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides (TG) as lipid droplets in the liver. Although lipid-metabolizing enzymes are considered important in NAFLD, the involvement of phospholipase D1 (PLD1) has not yet been studied. Here, we show that the genetic ablation of PLD1 in mice induces NAFLD due to an autophagy defect. PLD1 expression was decreased in high-fat diet-induced NAFLD. Subsequently, PLD1 deficiency led to an increase in hepatic TGs and liver weight. Autophagic flux was blocked in Pld1−/− hepatocytes, with decreased β-oxidation rate, reduced oxidation-related gene expression, and swollen mitochondria. The dynamics of autophagy was restored by treatment with the PLD product, phosphatidic acid (PA) or adenoviral PLD1 expression in Pld1−/− hepatocytes, confirming that lysosomal PA produced by PLD1 regulates autophagy. Notably, PLD1 expression in Pld1−/− liver significantly reduced hepatic lipid accumulation, compared with Pld1−/− liver. Thus, PLD1 plays an important role in hepatic steatosis via the regulation of autophagy.
- Published
- 2016